C�F CompoundsDOI: 10.1002/anie.200701988

Synthesis and Conformation of Multi-Vicinal FluoroalkaneDiastereoisomers**Luke Hunter, Alexandra M. Z. Slawin, Peer Kirsch,* and David O�Hagan*

The incorporation of fluorine atoms is a powerful method formodulating the properties of organic compounds.[1] Theselective introduction of one fluorine atom as a replacementfor hydrogen or a hydroxy group can confer importantproperties in medicinal chemistry[2] because of the particularproperties of the C�F bond, and perfluorination of alkaneshas led to a wealth of industrially useful compounds.[3]

Intermediate between these compound classes are partiallyfluorinated molecules, and they have been studied far lessowing to the lack of good synthesis methods and control inmultiple fluorine introduction. In this area we have beeninterested in exploring alkanes bearing multiple vicinalfluorine substituents (such as shown in Figure 1), a new

class of compounds with potential applications as perfor-mance molecules in organic materials, for example as novelliquid crystals. Placing single fluorines vicinal to each othergenerates stereogenic centers, and careful evaluation of theproperties of such molecules requires control in their syn-thesis. This stereochemical complexity is a key feature whichsets multi-vicinal fluoroalkanes apart from both their hydro-carbon and perfluorocarbon analogues.

Our initial investigations developed synthetic routes tothree-[4] and four-[5]vicinal-fluorine systems. Herein we reportthe preparation of three different diastereoisomers of a four-vicinal-fluorine motif (Figure 1, R=OTs, Ts= 4-methylphe-nylsulfonyl) and the evaluation of their relative conforma-tions in the solid and solution states. This study is the first for

this class of molecules and forms a basis for predicting moregenerally how multi-vicinal fluoroalkanes behave.

The first isomer of this series, the all-syn tetrafluorocompound 5a (Scheme 1), was synthesized in nine steps fromfluoro alkene 1.[5] The synthetic sequence was then adaptedfor the preparation of the anti-syn-anti isomer 5b and theracemic syn-syn-anti isomer 5c.[6]

Tetrafluoroalkanes 5a, 5b, and rac-5c were crystalline,and their structures were confirmed by single-crystal X-rayanalyses. In the structure of the all-syn isomer 5a[5] (Figure 2),

Figure 1. Three a,b,g,d-tetrafluoroalkane diastereoisomers.

Figure 2. Crystal structures of 5a–c. C white, F green, H blue, O red,S yellow. Dihedral angles (left to right) between vicinal fluorines:5a,[5]66.7, 59.7, and 66.78 ; 5b, 176.8, 66.9, and 176.88 ; 5c (only oneenantiomer shown), 74.7, 77.7, and 32.98. Selected coupling constantsfrom the 1H NMR spectra of 5a–c are given; values which suggestdifferences between the solid- and solution-state conformations arehighlighted in boxes. The solution conformation of 5c is obtained byrotation of one C�C bond (shown in pink) to give a longer zigzagcarbon chain.

[*] Dr. L. Hunter, Prof. A. M. Z. Slawin, Prof. D. O’HaganCentre for Biomolecular Sciences and School of ChemistryUniversity of St. AndrewsNorth Haugh, St. Andrews, Fife KY16 9ST (UK)Fax: (+44)1334-463808E-mail: do1@st-andrews.ac.uk

Dr. P. KirschMerck Ltd. Japan, Liquid Crystal Technical Center4084 Nakatsu, Aikawa-machi, Aiko-gun,243-0303 Kanagawa, (Japan)Fax: (+81)462-853-838E-mail: Peer_Kirsch@merck.co.jpHomepage: http://chemistry.st-and.ac.uk/staff/doh/group

[**] We thank the EPSRC for funding this research.

Supporting information for this article is available on the WWWunder http://www.angewandte.org or from the author.

AngewandteChemie

7887Angew. Chem. Int. Ed. 2007, 46, 7887 –7890 � 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

the fluoroalkyl portion of the molecule did not adopt anextended zigzag conformation: instead, the molecule prefer-red a C2-symmetric “bent” conformation which neverthelesspreserved gauche alignments[7] between each pair of vicinalfluorines, and also between the outer fluorines and the tosylester oxygen atoms.

As seen in the crystal structure[8] of isomer 5b (Figure 2),the fluoroalkyl moiety also has C2 symmetry, but in contrastwith 5a the chain of 5b adopts an extended zigzag con-formation in the solid state. This result is perhaps surprisingsince this extended conformation precludes two of thepossible three fluorine gauche relationships.[7]

The solid-state conformation of syn-syn-anti isomer rac-5c was also investigated. Although rac-5c is crystalline, X-rayanalysis was not straightforward because of poor crystalquality, substantial disorder, and the presence of two crystal-lographically independent, nonsymmetrical enantiomericcontributors which alternate throughout the solid-state struc-ture. However, a diffraction data set with acceptably lowdisorder was obtained. In the resulting solid-state structure ofrac-5c[8] (Figure 2), all three pairs of vicinal fluorines areapproximately gauche but the dihedral angles deviate con-siderably from 608. It thus appears that the aromatic tosylgroups dominate the crystal-packing interactions, with thefluoroalkyl chain apparently forced to adopt a somewhatstrained conformation. This result highlights an importantissue relating to the crystal structures of all three isomers 5a–c(Figure 2): Since the tosyl groups are essential for thecrystallinity of the materials, they must by definition domi-nate the crystal-packing interactions and may thereforeobscure the intrinsic conformational preferences of thefluoroalkyl chains themselves. Thus, the NMR spectra of5a–c were examined to gain information about their solutionconformations.

For compound 5a, the 3JHH and 3JHF values obtained fromthe 1H NMR spectrum were somewhat intermediate inmagnitude[9] (Figure 2), suggesting that 5a exhibits significant

conformational flexibility in solution at 298 K. However,despite this flexibility, the X-ray conformation still seems todominate, since the expected gauche alignments all givesmaller 3J values than the expected anti alignments. The1H NMR spectrum of 5a was also recorded at 215 K, but onlymarginal differences in the 3JHH and

3JHF values were found atthis lower temperature.[6]

In contrast with the somewhat ambiguous NMR spec-troscopy results obtained for isomer 5a, a clear pictureemerged of the solution conformation of 5b (Figure 2).[9] Inthis case, the conformation displayed in the X-ray structurewas found to dominate in solution at 298 K, as evidenced bythe more ideal 3JHF values which clearly reflect gauche andanti alignments consistent with the extended zigzag confor-mation. Thus, it seems that this conformation is intrinsicallyfavored by the fluoroalkyl chain itself, and is not a product ofcompeting crystal-packing forces in the solid state.

The hypothesis that crystal-packing forces are responsiblefor distortion of the fluoroalkyl chain of 5c is supported byevidence of its solution conformation (Figure 2). In this case,the 3JHH and

3JHF values obtained from the 1H NMR spectrumof 5c all fell quite clearly into gauche or anti categories,suggesting that one conformation is strongly preferred insolution; however, this solution conformation does not matchthe X-ray conformation. It seems that in solution, thefluoroalkyl chain of 5c foregoes one fluorine gauche inter-action so that a longer section of the carbon chain can adoptthe extended zigzag conformation.

To gain further insight into the behavior of multi-vicinalfluoroalkanes 5a–c, computational analyses were performed.Model calculations[10] on fluorohexanes 6a–c (Figure 3)indicate that of all three isomers in the linear zigzagconformation, 6b has the lowest-energy. Within the series6a–c, 6b is the only isomer where the linear conformationrepresents the global energy minimum, which is also reflectedin the crystal structure of 5b (Figure 2). For the all-syn isomer6a, the linear conformation is 6.50 kcalmol�1 higher in energy

Scheme 1. Synthesis of 5a,[5] 5b and rac-5c. Reagents and conditions:[6] a) Grubbs 2nd-generation catalyst, CH2Cl2, D ; b) KMnO4, MgSO4, EtOH, CH2Cl2,H2O, 0 8C; c) SOCl2, pyridine, CH2Cl2, room temperature; d) NaIO4, RuCl3, MeCN, H2O, room temperature; e) Bu4NF, MeCN, room temperature; f) H2SO4,H2O, tetrahydrofuran, RT; g) H2, Pd/C, MeOH, room temperature; h) TsCl, collidine, 50 8C; i) (MeOCH2CH2)2NSF3 (Deoxo-Fluor), CH2Cl2, D.

Communications

7888 www.angewandte.org � 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2007, 46, 7887 –7890

than the lowest-energy conformer, which corresponds to thecrystal structure of 5a (Figure 2). The lowest-energy confor-mer calculated for isomer 6c is similar to that for the solutionstructure determined by NMR spectroscopy of 5c, providingfurther support that the crystal structure of 5c (Figure 2) isdominated by packing of the tosyl groups.

The major conformational driving force for the structuresin Figure 3 appears to be avoidance of 1,3-F···F and 1,3-F···CH3 interactions. For the “linear” conformations, 6a hastwo g+g� interactions,[11] whereas 6c has only one, and 6bnone. From the sequence 6a!6c!6b it is estimated thateach g+g�-F···F interaction costs about 3.4 kcalmol�1 in stericstrain.[12] For the “bent” pair 6b and 6c, the main difference isa 1,3-F···CH3 interaction, costing 4.04 kcalmol�1. In thiscontext, the vicinal fluorine gauche effect (ca. 0.8 kcalmol�1)[7] has only a secondary influence.

To gain insight into conformational effects in moreextended sequences, the all-syn-CH3(CHF)nCH3 series wasstudied by computational analysis. For each of the homo-logues from n= 2–12, the energies and structures of the linearand the lowest-energy conformation were calculated at theMP2/6-311+G(2d,p)//B3LYP/6-31G(d)+ZPE level oftheory.[10] Only for n= 2 does the linear conformer representthe energy minimum. There is a clear, first-order relationshipbetween relative linearization energies and the number ofg+g�-F···F contacts,[6] with each such interaction incurring anenergetic price of approximately 3.0 kcalmol�1. In the lowest-energy conformation of the extended all-syn isomers (seeFigure 3 with n= 12), a helical arrangement is adopted whichplaces all the C�F bonds gauchewith uniform handedness andthus avoids any g+g�-F···F repulsions.

An additional stabilization of the linear-chain conforma-tion of the shorter all-syn- and possibly also of fragments ofthe longer oligofluoroalkanes (all-syn-CH3(CHF)nCH3)might arise from the formation of intermolecular H···F

hydrogen bridges.[6] The dimerization energies are difficultto interpret in a quantitative manner because of the largevariation in hydrogen-bond lengths and orientation, buttypical energies seem to be in the range of 1.0–1.6 kcalmol�1

per H···F contact. However, because of steric restrictions,[6]

the maximum dimerization energy is probably limited toabout 6–7 kcalmol�1 for linear all-syn fluoroalkanes.

In summary, we have used our recently describedsynthetic methodology[5] to prepare three unique diastereo-isomeric a,b,g,d-tetrafluoroalkanes, and the conformationalpreferences of each isomer in the solid and solution states hasbeen examined. It emerges that the avoidance of 1,3-repulsiveinteractions is the dominant conformational consideration inthese multi-vicinal fluorine compounds, with the fluorinegauche effect contributing a more subtle conformationalinfluence, and we have extrapolated our findings to extendedmulti-vicinal fluorine systems. This work provides the firstconformation study on this class of molecules and providesinformation on the behavior and properties of future perfor-mance molecules containing vicinal fluorine motifs.

Received: May 4, 2007Published online: September 4, 2007

.Keywords: conformation analysis · fluorine ·NMRspectroscopy ·organofluorine chemistry

[1] a) P. Kirsch, Modern Fluoroorganic Chemistry, Wiley-VCH,Weinheim, 2004 ; b) R. D. Chambers, Fluorine in OrganicChemistry, Blackwell, Oxford, 2004.

[2] a) F. M. D. Ismail, J. Fluorine Chem. 2002, 118, 27; b) P. Jeschke,ChemBioChem 2004, 5, 570.

[3] G. G. Hougham, P. E. Cassidy, K. Johns, T. Davidson, Fluoro-polymers : Synthesis and Properties, Kluwer Academic, NewYork, 1999.

[4] M. Nicoletti, D. OKHagan, A. M. Z. Slawin, J. Am. Chem. Soc.2005, 127, 482.

[5] L. Hunter, D. OKHagan, A. M. Z. Slawin, J. Am. Chem. Soc.2006, 128, 16422.

[6] See Supporting Information for further details.[7] a) N. C. Craig, A. Chen, K. H. Suh, S. Klee, G. C. Mellau, B. P.

Winnewisser, M. Winnewisser, J. Am. Chem. Soc. 1997, 119,4789; b) L. Goodman, H. Gu, V. Pophristic, J. Phys. Chem. A2005, 109, 1223.

[8] CCDC-645778 (5b) and CCDC-645779 (5c) contain the supple-mentary crystallographic data for this paper. These data can beobtained free of charge from the Cambridge CrystallographicData Centre via www.ccdc.cam.ac.uk/data request/cif. The datafor 5a can be found through ref. [5].

[9] Three-bond H–H and H–F coupling constants obey Karplusrelationships with the corresponding H�C�C�H and H�C�C�Fdihedral angles: “typical” 3JHH values are 1–3 Hz for gauchealignments and 6–8 Hz for anti alignments (see ref. [13]), while“typical” 3JHF values are 5–15 Hz for gauche alignments and 25–35 Hz for anti alignments (see ref. [14]).

[10] Gaussian03 (RevisionD.01): M. J. Frisch et al., see SupportingInformation. The minimum geometries were optimized on theB3LYP/6-31G(d) level of theory, and were verified to have onlypositive eigenfrequencies. The energies of the conformers werecalculated on the MP2/6-311+G(2d,p) level of theory, using theB3LYP/6-31G(d) geometries and zero-point energies. Theenergies of the dimers were calculated at the same level of

Figure 3. Left: The simplified model system 6. Middle: Calculatedlinear conformations and right: either minimum (6a, 6c) or next-higher energy conformation (6b). C gray, F green, H white; red arrowsindicate g+g�-F–F interactions.[11] Relative energies are in kcalmol�1.Inset: the model system all-syn-CH3(CHF)12CH3 with its helical mini-mum energy conformation.

AngewandteChemie

7889Angew. Chem. Int. Ed. 2007, 46, 7887 –7890 � 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org

theory and basis-set superposition error (BSSE)-corrected usingthe counterpoise method.

[11] Review on this type of steric interaction: R. W. Hoffmann,Angew. Chem. 1992, 104, 1147; Angew. Chem. Int. Ed. Engl.1992, 31, 1124.

[12] This result is in agreement with a previous computational studyon 1,3-difluoropropane: D. Wu, A. Tian, H. Sun, J. Phys. Chem.A 1998, 102, 9901.

[13] A. M. Ihrig, S. L. Smith, J. Am. Chem. Soc. 1970, 92, 759.[14] C. Thibaudeau, J. Plavec, J. Chattopadhyaya, J. Org. Chem. 1998,

63, 4967.

Communications

7890 www.angewandte.org � 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2007, 46, 7887 –7890